Serum tHcy Research Articles

Correlations Between Folate, B12, Homocysteine Levels, and Radiological Markers of Neuropathology in Elderly Post-Stroke Patients

Objective: To investigate serum levels of folate, B12, and total homocysteine (tHcy) in elderly post-stroke patients, and the possible correlations with radiological markers of neuropathology.Design: Cross-sectional study.Setting: Department of Neurology, Cardinal Tien Hospital.Subjects: Eighty-nine elderly post-stroke patients were enrolled for dietary assessment and blood tests. Neuroradiological assessment was done in 62 of these patients.Main Outcome Measures: Dietary folate and vitamin B12 intakes were evaluated by a 24-h recall system using a semi-quantitative questionnaire. Circulating levels of folate, B12, and tHcy were measured. Magnetic resonance imaging (MRI) or computed tomography (CT) was used for evaluation of brain lesions including infarction and atrophy.Results: Mean folate and B12 intakes of these post-stroke patients were 69% and 261% of the recommended dietary allowances (RDA), respectively. Inadequate folate levels, defined as serum folate < 6 ng/mL, was noted in 68% of these patients. Hyperhomocysteinemia levels (tHcy ≥15 μmol/L) were observed in 48%. According to tertiles of serum tHcy and folate levels, the rate of brain atrophy, but not brain infarctions, are significantly associated with elevated tHcy (P = 0.0126) and decreased folate levels (P = 0.0273). After adjustments for age, sex, disease status, brain infarctions and carotid stenosis, the odds ratio of brain atrophy was 9.8 (95% CI: 1.7–56.4, P = 0.0101) in the hyperhomocysteinemia group and 9.6 (95% CI: 1.1–81.3, P = 0.0377) in the low folate group (serum folate < 3.0 ng/mL) compared with the group with normal tHcy and folate levels. No significant association was noted between vitamin B12 levels and brain lesions.Conclusions: Our data shows that folate deficiency and hyperhomocysteinemia are prevalent in elderly post-stroke patients. These two conditions are strongly and independently associated with the development of brain atrophy.

Study of Homocysteine Concentration in Coronary Heart Disease Patients and Comparison of Two Determination Methods

Introduction: Elevated total homocysteine (tHCY) is a known risk factor for atherosclerotic vascular disease, but the mechanism is not well understood. The study was designed to estimate tHCY concentration and other risk factors in coronary heart disease (CHD) males, evaluating two different methods for tHCY measurement: gas chromatography-mass spectrometry (GC-MS) method and competitive immunoassay method. Materials and Methods: Fifty men, mean age 53.9 years with CHD and a body mass index (BMI) >25.0, were examined for tHCY concentrations, lipids, blood glucose, uric acid, complete blood picture and erythrocyte sedimentation rate and high-sensitive C-reactive protein (hsCRP). Biochemical and hematological indices were determined by routine methods, hsCRP – by immunometric chemiluminescence method, and tHCY – by two different methods: a gas chromatographic method, using GC-MS and a competitive immunoassay method on an Immulite device. Results: The mean values of the lipids showed moderate dyslipidemia while the other parameters were within reference range. Mean BMI was 28.5 ± 0.42. Values of tHCY determined by the immunoassay method were 13.2 ± 0.95 µmol/l, and determined by GC-MS – 14.6 ± 1.09 µmol/l. We found a linear agreement between the DPC and GC-MS sets of measurements (r = 0.87, p ≤ 0.001). The median tHCY concentrations measured by immunoassay werelower than those measured with GC-MS, but differences were insignificant. An agreement between the competitive immunoassay and the GC-MS method evaluated by the Bland and Altman method was found. tHCY was >15 µmol/l in 12 patients as determined by the competitive immunoassay, and in 15 patients by the GC-MS method. tHCY levels were between 10 and 15 µmol/l in 24 patients by the immunoassay and in 29 patients by the GC-MS method. Twenty-four percent of the patients with CHD have an ‘increased risk’ with tHCY >15 µmol/l, and 48% are in the ‘gray zone’ with tHCY levels between 10 and 15 µmol/l. Conclusions: 40.8% of the studied patients had increased tHCY levels, not associated with the other lipid and nonlipid risk factors. The closest conformity between GC-MS and immunoassay methods was observed for serum tHCY concentrations. The between-method comparison revealsthat the above-mentioned methods can be used interchangeably.

Functional COMT Val158Met Polymorphism, Risk of Acute Coronary Events and Serum Homocysteine: The Kuopio Ischaemic Heart Disease Risk Factor Study

BackgroundThe role of circulating levels of total homocysteine tHcy in the development of coronary heart disease (CHD) is still under debate. One reason for conflicting results between previous studies on homocysteine and heart diseases could be consequence of different interactions between homocysteine and genes in different study populations. Many genetic factors play a role in folate-homocysteine metabolism, like functional polymorphism (Val108Met) in the Catechol-O-methyltransferase (COMT) gene.Methodology and FindingsOur aim was to examine the role of COMT Val158Met polymorphism and interaction of this polymorphism with serum tHcy and folate concentration on the risk of acute coronary and events in middle-aged men from eastern Finland. A population-based prospective cohort of 792 men aged 46–64 years was examined as part of the Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up of 9.3 years, there were 69 acute coronary events in men with no previous history of CHD. When comparing the COMT low activity genotype with the others, we found an age and examination year adjusted hazard rate ratio (HRR) of 1.73 (95% confidence interval (CI), 1.07–2.79), and an age, examination year, serum LDL and HDL cholesterol, and triglyceride concentration, systolic blood pressure and smoking adjusted HRR of 1.77 (95% CI, 1.05–2.77). Although serum tHcy concentration was not statistically significantly associated with acute coronary events (HRR for the highest third versus others 1.52, 95% CI, 0.93–2.49), subjects with both high serum tHcy and the COMT low activity genotype had an additionally increased adjusted risk of HRR 2.94 (95% CI 1.50–5.76) as compared with other men.ConclusionsThis prospective cohort study suggests that the functional COMT Val158Met polymorphism is associated with increased risk of acute coronary events and it may interact with high serum tHcy levels.

Plasma B vitamins and their relation to the severity of chronic heart failure

Background: Total homocysteine (tHcy) has been linked to the severity of chronic heart failure (CHF). Elevated tHcy concentrations are mainly caused by folate and vitamin B-12 deficiencies.Objective: We hypothesized that folate and vitamin B-12 deficiencies can explain the relation between tHcy and the severity of CHF.Design: We investigated 987 CHF patients. All subjects underwent a physical examination and blood sampling. Cardiac catheterization was performed in 929 patients and echocardiography in 460 patients. Serum tHcy, folate, vitamin B-12, and N-terminal pro-B-type natriuretic-peptide (NT-proBNP) were measured and renal and hepatic function were studied.Results: tHcy increased with increasing New York Heart Association (NYHA) classes of heart failure (P < 0.001) and correlated with the left ventricular ejection fraction (EF; r = −0.150, P < 0.001). Contrary to the hypothesis, vitamin B-12 (P < 0.001) increased with NYHA class (P < 0.001) and was negatively correlated with EF (r = −0.080, P = 0.015). Folate showed no relation with NYHA class or EF. Comparable results were obtained for NT-proBNP (tHcy: r = 0.27, P < 0.001; vitamin B-12: r = 0.091, P = 0.004; folate: r = −0.045, P = 0.169). The correlations between tHcy, EF, and NT-proBNP were significantly stronger in patients without coronary artery disease (CAD) than in those with CAD. Regression analysis showed that tHcy, but not B vitamins, is a strong predictor of EF and NT-proBNP.Conclusions: This study showed that tHcy, but not folate and vitamin B-12, is related to clinical, echocardiographic, and laboratory variables of CHF, which indicates a relation between tHcy and the severity of CHF. This relation is stronger in patients without CAD. The lack of association of folate and the paradoxical relation of vitamin B-12 with CHF can possibly be explained by a disturbance in hepatic homeostasis.

Functional inference of the methylenetetrahydrofolate reductase 677 C &gt; T and 1298A &gt; C polymorphisms from a large-scale epidemiological study

Two functional single nucleotide polymorphisms, 677C > T and 1298A > C have been described for the methylenetetrahydrofolate (MTHFR) gene. Both are associated with reduced enzyme activity in vitro. For the 677T, but not the 1298C allele, significantly lower serum folate and higher plasma total homocysteine (tHcy) have been reported. We genotyped 10,034 middle-aged (50-64 years old) subjects and measured serum folate and tHcy. Within strata of 677 genotypes, 1,298 genotypes had significantly different serum folate and tHcy (P < or = 0.03 for all comparisons). Each additional 1298C allele reduced mean serum folate and increased mean tHcy, by (on average) 4.5 and 3.0%, respectively. In comparison, within strata of 1,298 genotypes, the increase from no, to one 677T-allele reduced serum folate and increased tHcy by, 7.1 and 6.3%, respectively. Lowest serum folate and highest tHcy level was found for the 677TT/1298AA genotype. The difference in tHcy was significantly larger at low folate than at high folate when genotypes 677TT/1298AA and 677CT/1298AA, 677CT/1298AC and 677CC/1298AC, and genotypes 677CT/1298AC and 677CT/1298AA were compared. We interpreted these data in the context of a model of the MTHFR enzyme that describes the enzyme as a dimer that mainly exist in six different configurations. The model reconciled the observed phenotypic effects of the 677/1,298 combination genotypes with previous in vitro measurements, and identified enzyme configurations that are sensitive to low folate levels. In conclusion, this report demonstrates functional inference of the MTHFR 677 C > T and 1,298 A > C polymorphisms from a large-scale epidemiological study.

The effect of two different doses comprising the simultaneous administration of intravenous B-complex vitamins and oral folic acid on serum homocysteine levels in hemodialysis patients

Several regimens using different doses of folic acid (FA) alone or supplemented with B-complex vitamins (BCVs) have been tested for their ability to reduce total homocysteine (tHcy) serum levels in hemodialysis (HD) patients. In the present study, we assessed the effect of two different doses comprising the simultaneous administration of intravenous (IV) BCVs and an oral FA supplementation on serum tHCy levels in HD patients. In a cohort of 49 patients (31 male, 18 female) undergoing chronic HD treatment for a mean of 40.0+/-40.7 months, serum concentrations of tHcy, folate and vitamin-B12 (vB12) were determined at the end of three sequential periods as follows: 20 weeks without any BCV and/or FA supplementation (period A), 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA once a week (period B), and 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA thrice a week (period C). An IV dose of BCVs consisting of a 5 mL solution containing vitamin B1 (250 mg), vitamin B6 (250 mg) and vitamin B12 (1.5 mg) was administered at the end of hemodialysis. Mean serum tHcy levels were significantly higher at the end of period A relative to levels at the end of periods B and C (35.8+/-23 micromol/L vs. 22.0+/-17.6 and 15.0+/-4.5 micromol/L, respectively; p<0.000001). Mean serum folate levels and mean serum vB12 levels were significantly lower at the end of period A relative to levels at the end of periods B and C (p<0.000001). Mean serum tHcy levels were lowest at the end of period C (p<0.000001 in comparison to periods A and B), and 26 of the 49 HD patients (67.3%) possessed tHcy levels below 16 micromol/L. In HD patients, high doses consisting of the simultaneous administration of IV BCVs and an oral FA supplementation resulted in the efficient reduction of serum tHcy levels.

A Single-Center, Double-Blinded, Randomized Controlled Study to Evaluate the Relative Efficacy of Sublingual and Oral Vitamin B-Complex Administration in Reducing Total Serum Homocysteine Levels

Reports correlating total homocysteine (tHcy) concentrations with arteriosclerosis have become a matter of interest amongst healthcare professionals and the public. Several commercial preparations of vitamin B complexes have been marketed as supplements intended to reduce elevated levels of tHcy. Among these preparations are those that have been specifically designed for sublingual administration. This study is designed to evaluate the relative efficacy of sublingually versus orally delivered vitamin B complex in reducing serum tHcy levels. Forty-one (41) subjects, between the ages of 50 and 80 years with total serum tHcy concentrations exceeding 11 micromol/L, were treated with a six-week regimen of vitamin B complex. Each B complex consisted of 1000 microg vitamin B12 (as methylcobalamin), 400 microg folate (as folic acid), and 5 mg vitamin B6 (as pyridoxine HCl). Participants in the study were randomized into two groups designated, retrospectively, as SL and PO. Members of group SL were given a sublingually delivered vitamin B complex and a matching orally delivered placebo. Members of group PO were given an orally delivered vitamin complex and a matching sublingually delivered placebo. A statistically significant reduction in tHcy values was observed in both groups upon completion of the 6-week protocol. There was no statistically significant difference in serum tHcy concentrations between SL and PO groups either before or after treatment, substantiating the idea that there is no difference in efficacy between the two methods of vitamin complex delivery.

Parallel changes in metabolite and expression profiles in crooked-tail mutant and folate-reduced wild-type mice

Anomalies in homocysteine (HCY) and folate metabolism are associated with common birth defects and adult diseases, several of which can be suppressed with dietary folate supplementation. Although supplementation reduces the occurrence and severity of neural tube defects (NTDs), many cases are resistant to these beneficial effects. The basis for variable response and biomarkers that predict responsiveness are unknown. Crooked-tail (Cd) mutant mice are an important model of folate-responsive NTDs. To identify features that are diagnostic for responsiveness versus resistance to dietary folate supplementation, we surveyed metabolite and expression levels in liver samples from folate-supplemented, folate-reduced and control diets in Cd mutant and wild-type adult females. Cd homozygotes had normal total homocysteine (tHcy) levels suggesting that folate suppresses NTDs through a mechanism that does not involve modulating serum tHcy levels. Instead, parallel changes in metabolite and expression profiles in folate-supplemented Cd/Cd homozygotes and folate-reduced+/+and Cd/+mice suggest that Crooked-tail homozygotes have a defect in the utilization of intracellular folate. Then, by combining these expression and metabolite profile results with published results for other models and their controls, two clusters were found, one of which included several folate-responsive NTD models and the other previously untested and presumably folate-resistant models. The predictive value of these profiles was verified by demonstrating that NTDs of Ski-/-mutant mice, whose profile suggested resistance to folate supplementation, were not suppressed with dietary folate supplementation. These results raise the possibility of using metabolite and expression profiles to distinguish folate-responsive and resistance adult females who are at risk for bearing fetuses with an NTD.

Folate, vitamin B12 and total homocysteine levels in neonates from Brazil

To determine folates, vitamin B12 and total homocysteine levels among neonates from mothers of low or high socioeconomic status. We carried out a cross-sectional transversal study comprising 143 neonates from two maternity hospitals in the city of Salvador, Northeast of Brazil. Cord blood samples were obtained at the time of delivery from newborns from low (group 1, n=77) or high (group 2, n=66) socioeconomic status. The vitamin B12 and folates were analyzed by electrochemiluminescence immunoassay and by a competitive test using a natural folate-binding protein (FBP), respectively. Total homocyteine levels were measured by fluorescence polarization immunoassay. Maternal environmental risk factors for pregnancy complications were obtained from all mothers. Only 2% of women from group 1 received prenatal care/vitamin supplementation, whereas almost all mothers from group 2 (96%) were properly followed. Anemia and/or infections pre- or during pregnancy was more prevalent among mothers of babies from group 1. Folate levels among newborns from group 1 and 2 were 7.38+/-2.71 and 8.83+/-4.06 ng/ml, respectively. No difference in the vitamin B12 levels was determined between groups. In addition, tHcy serum levels were higher among newborns from group 1 compared to those from group 2 (8.54+/-4.06 vs 6.35+/-1.33 micromol/l, respectively; P=0.005). These results demonstrate that unprivileged young woman has limited accesses to prenatal care, present high-risk factors that hamper both maternal and newborn health. Maternal and newborn health status could be improved by simply reinforcing the use of folate-enriched diet. The work presented illustrates the challenges that developing countries have to face in order to provide preventive adequate health care to the population at large.

Total serum homocysteine, folate and vitamin B12 in a Greek school age population

Moderate hyperhomocysteinemia is an independent risk factor for cardiovascular disease (CVD) even among children. The purpose of this study is to investigate for the first time the distribution and determinants of total serum homocysteine (tHcy) levels in healthy Greek children. tHcy, folate, B12 were measured in 524 children (275 boys and 249 girls) aged 6-15 years old from different socioeconomic status in Northern Greece. The geometric mean tHcy level for boys and girls was 7.8 (3.4-24.2) and 7.5 (3.9-29.0) micromol/L, respectively. Eighty one (15.4%) children had homocysteine levels above the upper reference limits (>10 micromol/L). The geometric mean serum tHcy level was significantly (P<0.001) increasing with age; 6.4 (3.4-11.2) micromol/L was found in the age group of 6-9 yr (group1), 7.2(4.1-22.1) micromol/L in the one of 10-12 yr (group 2) and 8.5 (3.9-29.0) micromol/L in the one of 13-15 yr (group 3). Serum folate levels were found to be statistically significant (P<0.001) between age group 1 and age group 3 [11.8 (4.66-20.00) vs. 7.5 (0.99-20.00)ng/mL) and between age group 2 and 3 [10.0 (1.82-20.0) vs. 7.5 (0.99-20.00)ng/mL]. Vitamin B12 levels were significantly (P<0.001) different in the three age groups [1048 (117-2000), 805 (296-2000), 700 (214-2000)pg/mL] respectively. Age, BMI, waist circumference (WC), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively correlated with tHcy, whereas serum folate and vitamin B12 were negatively correlated. No association was found between tHcy levels and parental education status. In multiple linear regression analysis only age (Beta: 0.248, 95%, CI: (0.159-0.361), P<0.05) and folate (Beta: 0.347, 95%, CI: [(-0.206)-(-0.118)], P<0.05) were found significantly and independently associated with tHcy. tHcy levels were increasing with age and boys were found to have slightly higher levels than girls. Age and folate levels were the most significantly and independently determinants associated with tHcy. Children with tHcy levels above the upper reference limits (>10 micromol/L) were found to be correlated with BMI, WC, SBP, serum folate and vitamin B12 levels. These children should be encouraged to include high folate food items in their diet and where necessary folate supplements should be recommended. In addition, more prospective studies are necessary in order to evaluate the relationship of tHcy and CVD risk factors in children of our region.

Fuzzy role of hyperhomocysteinemia in hemodialysis patients’ mortality

Recent studies give contradictory data regarding the role of hyperhomocysteinemia (hyperHcy) in cardiovascular (CV) morbidity and mortality in hemodialysis (HD) patients. The aims of the present study were to detect the most powerful variables associated with hyperHcy as well as to evaluate the relationship between hyperHcy and CV morbidity and mortality. The prospective follow-up study of 113 patients (52 males, aged 55.2 ± 13.1 years) maintained by HD for 81.9 ± 56.9 months at our Institute was carried out over 55 months. Fifty-seven (50.4%) of the examined patients were supplemented with water-soluble vitamins including folic acid and vitamin B complex pills or ampoules. Total serum Hcy level was determined by high-performance liquid chromatography, while serum folic acid and vitamin B 12 were measured by radioimmunoassay. The multivariate analysis showed HD duration ( r = 0.608; P = 0.02) and folic acid serum level ( r = –0.580; P = 0.03) to be significant predictors of serum tHcy concentration. The multivariate Cox regression analysis of CV mortality revealed diabetes mellitus and heart failure as the most powerful positive predictors, while creatinine, albumin and vitamins intake therapy were negative predictors of CV mortality. Long-term supplementation with the usual doses of vitamins is followed with increased survival in hemodialysis patients. Although total serum Hcy level was not found to be a predictor of overall and CV mortality, the role of hyperHcy. as risk factor for CVD cannot be excluded in hemodialysis patients.

Relationship Between Homocysteine and Mortality in Chronic Kidney Disease

The relationship between total homocysteine (tHcy) and outcomes has not been investigated in patients with chronic kidney disease stages 3 to 4. The Modification of Diet in Renal Disease Study was a randomized, controlled trial of 840 patients. Serum tHcy was measured in frozen samples collected at baseline (n=804). Survival status and cause of death were obtained from the National Death Index. To evaluate its association with all-cause and cardiovascular disease (CVD) mortality, tHcy was evaluated both as tertiles (<14.7, 14.7 to 19.5, > or =19.6 micromol/L) and as a continuous variable (per 10/micromol/L). Participants had a mean age of 52+/-12 years and glomerular filtration rate (GFR) of 33+/-12 mL/min per 1.73 m2; 60% were male, and 85% were white. During a median follow-up of 10 years, 195 (24%) died from any cause, and 118 (15%) from CVD. The level of GFR was lower and proteinuria higher in the highest tHcy tertile. There was no association between the highest tertile of tHcy and all-cause (hazard ratio [HR]; 95% confidence interval [CI[, 1.32, 0.94 to 1.85) or CVD (HR; 95% CI, 1.50, 0.96 to 2.34) mortality in univariate analyses; this association was further attenuated by adjustment for GFR (HR; 95% CI all-cause, 1.04, 0.72 to 1.51; CVD, 1.20, 0.73 to 1.95). There was no association between tHcy as a continuous variable and all-cause (0.98, 0.83 to 1.16) or CVD (1.04, 0.85 to 1.27) mortality. Hyperhomocystinemia does not appear to be a risk factor for all-cause or CVD mortality in the Modification of Diet in Renal Disease Study. Prior studies demonstrating an association between tHcy and CVD risk may have inadequately adjusted for the confounding effects of kidney function.

Serum homocysteine concentration as a marker of nutritional status of healthy subjects in Crete, Greece

Dietary habits are an important determinant of serum homocysteine (tHcy), which may be a marker rather than a cause of progression of the atherosclerotic process. The aim of the present study was to evaluate the nutritional status, and to determine the serum tHcy concentrations in healthy subjects who live in rural areas of Crete, and who theoretically follow a contemporary Mediterranean-style diet. Serum tHcy, folate, vitamin B(12), creatinine, glucose, and the lipid profile, were measured in 203 (141 men and 62 women) healthy subjects, aged 33-78 years. The major risk factors for cardiovascular disease such as age, gender, cigarette smoking, obesity were recorded and dietary data were assessed using a 3-day weighed food intake record. Our population had high serum tHcy, low serum folate concentrations and lower than the traditional Cretan dietary folate intake [median (range): 12.0 (3.6-44.7) micromol L(-1), 7.9 (1.9-15.5) ng mL(-1) and 241 (68-1106) microg, respectively]. Dietary intake of fibre, omega-3, and mono- or/ polyunsaturated fatty acids was also low. An inverse relation was observed between serum tHcy concentrations and serum folate (r = -0.28; P < 0.01) and vitamin B(12) levels (r = -0.33; P < 0.001). Nowadays, the Cretan diet has changed towards a more westernized eating pattern. Given the analytic difficulties in determining the amount of folate in food and the inverse correlation between serum tHcy and folate levels, serum tHcy concentrations may be a useful marker for nutritional status, especially folate deficiency, in healthy subjects.

Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population

Homocysteine concentrations are influenced by vitamin status and genetics, especially several polymorphisms in folate-metabolizing genes. We examined the interactions and associations with serum total homocysteine (tHcy) and folate concentrations of polymorphisms in the following folate-metabolizing genes: methylenetetrahydrofolate reductase (MTHFR), reduced folate carrier 1 (RFC1), and glutamate carboxypeptidase II (GCPII). Healthy volunteers (436 men and 606 women; mean age: 77.9 y) were randomly selected from among residents of Oxford, United Kingdom. We determined the individual effects and interactions of the MTHFR 677C-->T, MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms on serum tHcy and folate concentrations. Subjects with the MTHFR 677TT genotype had higher serum tHcy concentrations than did those with the MTHFR 677CC genotype (P < 0.001), and this effect was greater in subjects with low serum folate status (P for interaction = 0.026). The MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms had no individual effects on serum tHcy or folate concentrations. There was no interactive effect of the MTHFR 677C-->T and MTHFR 1298A-->C polymorphisms on tHcy concentrations. An interaction (P = 0.05) was observed between the MTHFR 677TT and RFC1 80GG genotypes, whereby persons with this genotype combination had a mean (+/-SEM) serum tHcy concentration (18.5 +/- 1.2 micromol/L) that was 5.1 micromol/L greater than the mean value of 13.4 +/- 0.2 micromol/L for the whole population. Folate and tHcy concentrations were not affected individually by the MTHFR 1298A-->C, RFC1 80G-->A, or GCPII 1561C-->T polymorphisms or by combinations of the MTHFR 677C-->T and MTHFR 1298A-->C genotypes. An interaction between the MTHFR 677TT and RFC1 80GG genotypes was observed whereby persons with this combination had higher serum tHcy.

Association between plasma homocysteine concentrations and extracranial carotid stenosis

BACKGROUNDIncreasing epidemiologic data support a relationship between elevated plasma total homocysteine levels and an increased risk for vascular disease. Higher plasma total homocysteine (tHcy) levels have been associated with extracranial carotid atherosclerosis and cerebral infarction in whites. However, data regarding such associations are limited for Asians. This study examined the association between tHcy level and carotid stenosis in Iranian subjects.PATIENTS AND METHODSIn this retrospective study, the subjects were 158 patients with ischemic stroke, including 105 with a normal tHcy level and 53 with a high tHcy level. We investigated the extracranial carotid arteries by ultrasonography and measured serum tHcy by the ELISA method in these two groups.RESULTSWe found no meaningful association between a high tHcy level and carotid stenosis.DISCUSSIONThe lack of any meaningful difference in carotid stenosis between patients with normal and elevated tHcy levels is probably due to the low frequency of extracranial disease in the Asian population and to the nature of homocysteine atherosclerosis.

Hyperhomocysteinemia in chronic renal failure patients: relation to tissue factor and platelet aggregation

A moderate increase in plasma total homocysteine (t-hcy) is considered to be an independent risk factor for cardiovascular disease (CVD) in general population. One of the mechanisms by which hyperhomocysteinemia contributes to cardiovascular risk has been explained to be the increased thrombotic potential. Elevated t-hcy levels were also reported in chronic renal failure patients because the renal function is a major determinant of serum t-hcy levels. We measured serum hcy and ADP-induced platelet aggregation and plasma tissue factor as a major activator of the coagulation cascade in hemodialysis (HD), peritoneal dialysis (PD) and early stage chronic renal failure (early stage CRF) patients who are not receiving dialysis and compared with those of control. In addition, we also determined serum vitamin B12 and folat levels which are the important factors regulating the metabolism of t-hcy. Hcy levels in all patient groups were significantly higher (HD: 20.42 +/- 1.91 micromol/l, PD: 35.47 +/- 6.30, early stage CRF: 24.39 +/- 3.06) than the normal levels (10.74 +/- 0.74) in spite of standard multivitamin supplementation. The highest t-hcy values were found in peritoneal dialysis patients. Vitamin B12 levels in hemodialysis/peritoneal dialysis patients and folat levels in hemodialysis/early stage CRF patients were also significantly above those of control. On the other hand, the significant elevations in plasma tissue factor concentration were found in all patient groups (HD: 331.4 +/- 31.3 pg/ml, PD: 306.0 +/- 30.0, early stage CRF: 277.2 +/- 25.5 and 69.5 +/- 13.5). t-hcy levels were positively correlated with creatinine (r: 0.791 p < 0.002) and tissue factor levels (r: 0.526 p < 0.05) in only early stage CRF group. The association between t-hcy and tissue factor persisted after these two parameters were adjusted for creatinine (r: 0.649 p < 0.05). On the other hand the same correlations were not observed in dialysis patient groups. In spite of the high tissue factor levels, ADP-induced platelet aggregations were found to be lower in all patient groups (HD: 102.6 +/- 6.7, PD: 98.6 +/- 7.6 and Early stage CRF: 84.9 +/- 7.6) than controls (154.9 +/- 13.7). These results suggest that hyperhomocysteinemia and increased tissue factor level are present in patients with renal failure, despite supplementation with vitamin B6 and B12 and folat. However, elevated levels of these thrombogenic factors are not linked with platelet aggregation.

Serum homocysteine levels and paraoxonase 1 activity in preschool aged children in Greece

Over the past decade, it has been well established that elevated total serum homocysteine (tHcy) in adults is associated with increased risk of cardiovascular and thromboembolic diseases. Since risk factors for such diseases are established at a young age, the aim of the present study was to measure serum tHcy levels in 134 (71 boys, 63 girls) randomly selected healthy preschool children aged 4-6 years (mean 5.1), and to investigate possible correlation with paraoxonase 1 (PON1) activity, an antioxidant enzyme that contributes to the antiatherogenic properties of high-density lipoprotein (HDL). tHcy was determined using an IMX tHcy assay (FPIA). PON1 was measured by a spectrophotometric method at 412 nm. Mean serum tHcy was 7.71+/-2.35 mumol/L. A relatively significant percentage (15.6%) of boys and girls had elevated serum tHcy levels (>10 mumol/L). tHcy levels were slightly higher in girls compared to boys (8.20+/-2.80 vs. 7.29+/-1.79 mumol/L, respectively; p<0.11). There was no significant interaction between age and tHcy levels. Mean PON1 activity was 124.86+/-66.62 U/L. No statistical difference in enzyme activity was observed between boys and girls (126.81+/-69.99 vs. 121.74+/-64.78 U/L) was observed. On the contrary, a weak negative relationship between tHcy concentration and PON1 activity was detected, with Pearson's correlation coefficient of r=-0.27. The significant percentage of elevated tHcy levels observed in healthy preschool cases and the negative tHcy correlation with PON1 activity are reported for the first time. Since children with a family history of cardiovascular disease have higher levels of serum Hcy, tHcy screening in children, even of this age, in relation to other parameters, such the protective PON1, might prove a useful prevention procedure for the genetic risk of premature atherosclerosis.

Trends in Serum Folate, RBC Folate, and Circulating Total Homocysteine Concentrations in the United States: Analysis of Data from National Health and Nutrition Examination Surveys, 1988–1994, 1999–2000, and 2001–2002

Folate intakes increased dramatically after folic acid fortification. We investigated the changes in serum folate, RBC folate, and total homocysteine (tHcy) concentrations utilizing data from National Health and Nutrition Examination Surveys (NHANES) 1988-2002. NHANES 1988-2002 were based on a stratified, multistage, probability sampling design conducted among civilian U.S. residents. The current study included 17,144, 17,213, and 11,415 measurements for serum folate, RBC folate, and tHcy, respectively. Overall, geometric mean serum folate concentrations were 149.6 and 129.8% higher in 1999-2000 and 2001-2002, respectively, than in 1988-1994 (P < 0.0001). Sex-, age-, and race-ethnicity-adjusted serum folate was significantly lower in 2001-2002 than in 1999-2000 (10.4%, P < 0.0002). The prevalence of low serum folate decreased from 18.4% in 1988-1994 to 0.8% in 1999-2000 and to 0.2% in 2001-2002 (P < 0.0001). RBC folate increased from 391 nmol/L in 1988-1994 to 618 nmol/L in 1999-2000, and to 611 nmol/L in 2001-2002. Consequently, the prevalence of low RBC folate decreased from 45.8% in 1988-1994 to 7.3% in 1999-2000 and to 7.1% in 2001-2002 (P < 0.0001). Although, RBC folate status improved after folic acid fortification in all race-ethnicities, the prevalence of low RBC folate ( approximately 20.5%) continues to be high in non-Hispanic blacks. Age-, sex-, and race-ethnicity-adjusted tHcy declined from 9.5 micromol/L in 1988-1994 to 7.6 mumol/L in 1999-2000 and to 7.9 micromol/L in 2001-2002. Although folic acid fortification contributed to significant improvement in folate status, serum folate concentrations have declined recently. This may be attributable to lower folic acid intakes.

Factors Associated with Hyperhomocysteinemia After Renal Transplantation

Recent studies show that clinically stable renal transplant recipients have an increased prevalence of hyperhomocysteinemia (hyperHcy), but the mechanism of this disorder has not yet been elucidated. The aim of the present study was to evaluate the factors associated with hyperHcy after a successful renal transplantation. In 106 stable renal transplant recipients, total serum Hcy level (tHcy), folate, total protein, serum creatinine concentration, creatinine clearance, lipid status, body weight (BW), body mass index (BMI), and body fat (BF) were determined. The mean doses of cyclosporine, prednisolone, and azathioprine (mg/kg/day) were recorded. The mean serum tHcy level was significantly higher in renal transplant patients than in healthy controls (22.02 ± 8.02 versus 13.0 ± 3.3 μmol/L; p < 0.001), and the incidence of patients with hyperHcy was 82%. Comparison of the group of 20 patients with tHcy level <15 μmol/L and the group of 86 patients with tHcy level >15 μmol/L revealed that the latter was significantly older, heavier, had been longer on dialysis before renal transplantation, and had older donors and poorer renal graft function. Significant correlation was found between tHcy level and recipient age, dialysis duration, BW, creatinine clearance, serum creatinine, and folate concentration. However, multivariate analysis indicated that creatinine clearance (p = 0.025) and BW (p = 0.03) were the only determinants of elevated total Hcy level in renal transplant recipients. HyperHcy persists after successful kidney transplantation in the majority of renal transplant recipients, and its appearance is primarily associated with creatinine clearance and body weight.

Th-P16:417 Statins inhibit vascular valcification by restoring GAS6-AXL survival pathway in human aortic smooth muscle cells

Background: Hyperhomocysteinemia may constitute an independent risk factor for cardiovascular disease and may promote atherothrombosis. Psoriasis is one of the diseases associated with increased atherothrombosis. The aim of the present study was to examine serum total homocysteine (tHcy) level and its relationships with atherothrombotic markers. Methods: The study group included 30 patients with psoriasis (17 females and 13 males) with a mean age of 34.2 (age range: 27–40) and 30 sex and age matched healthy volunteers (15 females and 15 males) with a mean age of 36.7 (age range: 26–48). The concentrations of lipids, lipoproteins, acute phase reactants, tHcy and atherothrombotic markers [fibronectin, soluble vascular adhesion molecules-1 (sVCAM-1), soluble intercellular adhesion molecules-1 (sICAM-1), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), autoantibodies against oxidized LDL (AuAb-oxLDL)] were determined. Results: The mean levels of serum tHcy, fibrinogen, fibronectin, sICAM, PAI-1 and AuAb-oxLDL were increased in patients whereas tPA, vitamin B12 and folate levels were decreased significantly. Increased levels of sVCAM were not statistically significant. tHcy levels were negatively correlated with vitamin B12 (r=−0.40, P=0.027) and positively correlated with PAI-1 and AuAb-oxLDL levels (r=0.46, P=0.011; r=0.39, P=0.035, respectively). Conclusions: It was concluded that the increased homocysteine concentration and altered endothelial cell-mediated proteins associated with increased lipids and LDL oxidation may play an important role for the development of atherothrombotic complications with psoriasis.